Phosphoinositide 3-kinases (“PI3Ks”) comprise a family of lipid kinases that catalyze the synthesis of the phosphatidylinositol (“PI”) second messagers PI(3)P (“PIP”), PI(3,4)P2 (“PIP2”), and PI(3,4,5)P3 (“PIP3”). (Fruman et al., “Phosphoinositide kinases”, Annu. Rev. Biochem. 67 (1998), pp. 481-507; Knight et al., “A Pharmacological Map of the PI3-K Family Defines a Role for p110α in Insulin Signaling”, Cell 125 (2006), pp. 733-747.) In the appropriate cellular context, these lipids mediate diverse physiological processes including cell growth, survival, differentiation, and chemotaxis. (Katso et al., “Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer”, Annu. Rev. Cell Dev. Biol. 17 (2001), pp. 615-675.) The PI3K family comprises at least 15 different lipid and serine/threonine kinases, sub-classified by structural homology, with distinct substrate specificities, expression patterns, and mode of regulation. Class I PI3Kα is the main PI3-kinase isoform in cancer, and consists of catalytic (p110α) and adapter (p85) subunits. (Stirdivant et al., “Cloning and mutagenesis of the p110α subunit of human phosphoinositide 3′-hydroxykinase”, Bioorg. Med. Chem. 5 (1997), pp. 65-74.)
The 3-phosphorylated phospholipid, PIP3, acts as a second messenger recruiting kinases with lipid binding domains (including plekstrin homology (“PH”) regions), such as Akt, the product of the human homologue of the viral oncogene v-Akt, and phosphoinositide-dependent kinase-1 (“PDK1”). (Vivanco & Sawyers, “The Phosphatidylinositol 3-Kinase-Akt Pathway In Human Cancer”, Nature Reviews Cancer 2 (2002), pp. 489-501.) Binding of Akt to PIP3 induces Akt to translocate to the plasma membrane, bringing Akt into contact with PDK1, which activates Akt. The tumor-suppressor phosphatase, PTEN, dephosphorylates PIP3, and therefore acts as a negative regulator of Akt activation. The PI3Ks, Akt and PDK1 are important in the regulation of many cellular processes including cell cycle regulation, proliferation, survival, apoptosis and motility and are significant components of the molecular mechanisms of diseases such as cancer, diabetes and immune inflammation. Functional loss of PTEN (the most commonly mutated tumor-suppressor gene in cancer after p53), oncogenic mutations in the PIK3CA gene encoding PI3Kα, amplification of the PIK3CA gene and overexpression of Akt have been established in many malignancies. (see, for example, Samuels, et al., “High frequency of mutations of the PIK3CA gene in human cancers”, Science 304 (2004), p. 554; Broderick et al., “Mutations in PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas”, Cancer Research 64 (2004), pp. 5048-5050.) Therefore, the deregulation of PI3k and the upstream and downstream components of this signaling pathway is one of the most common deregulations associated with human cancers and proliferative diseases. (Parsons et al., Nature, 436 (2005), p. 792; Hennessey et al., Nature Rev. Drug Disc. 4 (2005) 988-1004.)
PI3Kα is thus an attractive target for cancer drug development because PI3Kα inhibitors would be expected to inhibit proliferation and summon resistance to cytotoxic agents in cancer cells.